Abstract
ObjectiveTo evaluate the effects of vitamin E, pioglitazone, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with non-alcoholic fatty liver disease (NAFLD).DesignA network meta-analysis.Data SourcesPubMed, Embase, Cochrane Library, and Web of Science databases from their inception until September 1, 2021.Eligibility Criteria for Selecting StudiesRandomized controlled trials (RCTs) comparing the effects of four different drugs in patients with NAFLD were included. All superiority, non-inferiority, phase II and III, non-blinded, single-blinded, and double-blinded trials were included. Interventions of interest included vitamin E (α-tocopherol and δ-tocotrienol), pioglitazone, three kinds of GLP-1 receptor agonists (liraglutide, semaglutide, and dulaglutide), four SGLT2 inhibitors (dapagliflozin, empagliflozin, ipragliflozin, and tofogliflozin), and comparisons of these different drugs, and placebos.Main Outcome MeasuresThe outcome measures included changes in non-invasive tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), controlled attenuation parameter (CAP), enhanced liver fibrosis (ELF) score, liver fat content (LFC), and keratin-18 (K-18)] and invasive tests [fibrosis score and resolution of non-alcoholic steatohepatitis (NASH)].ResultsTwenty-seven trials including 3,416 patients were eligible for inclusion in the study. Results refer to vitamin E, pioglitazone, GLP-1 receptor agonists, and SGLT2 inhibitors. First, placebos were used as a reference. δ-Tocotrienol was superior to placebo in decreasing the GGT level. Semaglutide, ipragliflozin, and pioglitazone induced a significantly higher decrease in the ALT level than a placebo. Semaglutide, pioglitazone, and dapagliflozin were superior to placebo in decreasing the AST level. Tofogliflozin and pioglitazone induced a significantly higher decrease in the K-18 level than a placebo. Liraglutide was superior to placebo in decreasing CAP. Liraglutide, pioglitazone, and vitamin E induced a significantly higher increase in resolution of NASH than a placebo. As for pairwise comparisons, semaglutide and pioglitazone were superior to liraglutide in decreasing the ALT level. Semaglutide induced a significantly higher decrease in the ALT level than dulaglutide. Semaglutide was obviously superior to empagliflozin, liraglutide, dulaglutide, and tofogliflozin in decreasing the AST level. Pioglitazone induced a significantly higher decrease in the GGT level than ipragliflozin. δ-Tocotrienol was superior to liraglutide in decreasing the GGT level. Tofogliflozin and pioglitazone induced a significantly higher decrease in the K-18 level than dulaglutide. Pioglitazone was superior to vitamin E in increasing the resolution of NASH. Furthermore, liraglutide treatment had the highest SUCRA ranking in decreasing CAP and ELF scores and increasing the resolution of NASH. Pioglitazone treatment had the highest SUCRA ranking in decreasing LFC and fibrosis scores. Tofogliflozin treatment had the highest SUCRA ranking in decreasing K-18, while dapagliflozin treatment had the highest SUCRA ranking in decreasing the GGT level. Semaglutide treatment had the highest SUCRA ranking in decreasing the levels of ALT and AST.ConclusionThe network meta-analysis provided evidence for the efficacy of vitamin E, pioglitazone, SGLT2 inhibitors, and GLP-1 receptor agonists in treating patients with NAFLD. To find the best guide-level drugs, it is necessary to include more RCTs with these off-label drugs, so that patients and clinicians can make optimal decisions together.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero, identifier: CRD42021283129.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is defined by the presence of steatosis in more than 5% of hepatocytes, in association with metabolic risk factors and in the absence of excessive alcohol consumption (≥30 g/day for men and ≥20 g/day for women) or other chronic liver diseases [1]
Vitamin E and pioglitazone have been endorsed by the current guidelines (Asia-Pacific Working Party on NAFLD) but not yet approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines in treating NAFLD linked with diabetes mellitus [11]
Alanine Aminotransferase Our NMA included 20 Randomized controlled trial (RCT) reporting the administration of vitamin E, pioglitazone, three Glucagon-like peptide1 (GLP-1) receptor agonists, and four sodium-glucose cotransporter-2 (SGLT2) inhibitors among 1,506 patients
Summary
Non-alcoholic fatty liver disease (NAFLD) is defined by the presence of steatosis in more than 5% of hepatocytes, in association with metabolic risk factors (in particular, obesity and type 2 diabetes) and in the absence of excessive alcohol consumption (≥30 g/day for men and ≥20 g/day for women) or other chronic liver diseases [1]. It is extremely important to treat NAFLD with or Abbreviations: NAFLD, non-alcoholic fatty liver disease; CAP, controlled attenuation parameter; LFC, liver fat content; ELF, enhanced liver fibrosis; K-18, keratin-18 (K-18) M30 fragment; ALT, alanine aminotransferase; AST, aspartate aminotransferase; FDA, Food and Drug Administration; EMA, European Medicines Agency; GGT, gamma-glutamyl transferase; GLP-1, glucagon-like peptide-1; HCC, hepatocellular carcinoma; HOMA-IR, homeostatic model assessment for insulin resistance; PPARγ, peroxisome proliferator-activated receptor γ; SGLT2, sodium-glucose cotransporter-2; RCT, Randomized controlled trial; NICE, the United Kingdom’s National Institute for Health and Clinical Excellence; NASH, non-alcoholic steatohepatitis. Pioglitazone is a peroxisome proliferator-activated receptor γ (PPARγ) agonist, which can protect the liver by improving insulin resistance in patients with NAFLD and with type 2 diabetes mellitus. Vitamin E has been found to be useful for patients with NAFLD and without type 2 diabetes [18]
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